4-Hydroxyphenylthio derivatives, their preparation and their use for the preparation of aminoalkoxyphenylsulphonyl derivatives

ABSTRACT

The subject of the invention is 4-hydroxyphenylthio derivatives of general formula: ##STR1## in which: R 1  and R 2 , which are identical or different, each represent hydrogen, a methyl or ethyl radical or a halogen atom, 
     R represents a (C 1  -C 6 ) alkyl, (C 3  -C 6 ) cycloalkyl or phenyl radical, 
     R 3  represents hydrogen or a halogen atom, 
     X represents --O--, --S-- or --NR 4  -- in which R 4  represents hydrogen or a (C 1  -C 4 ) alkyl group, 
     useful as synthetic intermediates, especially for the preparation of aminoalkoxyphenylsulphonyl derivatives which are pharmaceutically active compounds.

This is a divisional of application Ser. No. 08/302,427, filed Sep. 8,1994, now U.S. Pat. No. 5,508,431, which is a divisional of applicationSer. No. 08/080,171 filed Jun. 23, 1993, now U.S. Pat. No. 5,401,855issued Mar. 28, 1995.

The present invention relates generally to new substituted thiophenols,to a process for their preparation and to their use as syntheticintermediates.

More precisely, the subject of the invention is the 4-hydroxyphenylthioderivatives of general formula: ##STR2## in which: R₁ and R₂, which areidentical or different, each represent hydrogen, a methyl or ethylradical or a halogen atom such as chlorine, bromine or iodine,

R represents a (C₁ -C₆) alkyl, (C₃ -C₆) cycloalkyl or phenyl radical,

R₃ represents hydrogen or a halogen atom such as chlorine or bromine,

X represents --O--, --S-- or --NR₄ --in which R₄ represents hydrogen ora (C₁ -C₄) alkyl group.

Thus, taking account of the above values, R can especially represent amethyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl orcyclopropyl radical.

The compounds of formula 1 in which R₁ and R₂ each represent hydrogen,R₃ represents hydrogen or a chlorine atom and X represents a radical--NR₄ -- in which R₄ represents hydrogen or a methyl radical, constitutepreferred compounds according to the invention.

Likewise, a particularly preferred series of compounds is represented bythe formula I in which X represents a group --NR₄ --.

In the above formula I, the 4-hydroxyphenylthio group can be in position2 of the heterocycle and the group R in position 3, or vice versa, so asto form substituted 3-R-2-(4-hydroxyphenylthio)benzofurans,-benzothiophenes or -indoles or substituted2-R-3-(4-hydroxyphenylthio)benzofurans, -benzothiophenes or -indoles.However, the substituted 3-R-2-(4-hydroxyphenylthio)indoles of formula Iare preferred.

The compounds of the invention are found to be particularly useful asintermediates, especially for the preparation of4-hydroxyphenylsulphonyl derivatives of general formula: ##STR3## inwhich R, R₁, R₂, R₃ and X have the same meaning as above.

These compounds of formula II can be themselves widely used asintermediates in the preparation of various products, especially for thefinal synthesis of aminoalkoxyphenylsulphonyl derivatives of generalformula: ##STR4## in which R, R₁, R₂, R₃ and X have the same meaning asabove, A represents a (C₂ -C₅) alkylene or 2-hydroxypropylene radical,and Am represents a substituted amino radical, especially:

a radical of formula: ##STR5## in which R₅ represents hydrogen or a (C₁-C₈) alkyl radical and R₆ represents a (C₁ -C₈) alkyl radical or aradical of formula:

    --Alk--R.sub.7

in which Alk represents a single bond or a (C₁ -C₅) alkylene radical andR₇ represents a pyridyl, phenyl, 2,3-methylenedioxyphenyl or3,4-methylenedioxyphenyl radical or a phenyl group substituted by one ora number of identical or different substituents selected from halogenatoms, (C₁ -C₄ ) alkyl groups or ( C₁ -C₄) alkoxy groups or R₅ and R₆,when they are taken together, represent a (C₃ -C₆) alkylene oralkenylene radical, optionally interrupted by --O--, --NH--, --N═ or--NR₈ --, R₈ representing a (C₁ -C₄) alkyl, phenyl or diphenylmethylradical, so that R₅ and R₆, taken with the nitrogen atom to which theyare attached, can especially represent a pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, 4 -methylpiperazinyl, 4-phenylpiperazinyl or1H-imidazolyl radical,

a group of formula: ##STR6## in which R₅ has the same meaning as above,R₉, R'₉ and R"₉, which are identical or different, each representhydrogen, a halogen atom, such as chlorine or bromine, or a (C₁ -C₄)alkyl or (C₁ -C₄) alkoxy group, and n and m, which are identical ordifferent, each represent 0, 1, 2 or 3, and for the preparation of theirpharmaceutically acceptable salts.

Such aminoalkoxyphenylsulphonyl derivatives of formula III have beendescribed, especially in Patents or Patent Applications EP-A-0,302,793,0,382,618, 0,382,628 and 0,382,629.

These compounds have been shown to be particularly advantageous fortheir therapeutical applications, especially for their inhibitingproperties on calcium translocation and for their bradycardic,hypotensive or antiadrenergic properties which make them useful in thetreatment of certain pathological syndromes of the cardiovascularsystem, in particular in the treatment of angina pectoris, hypertension,arrhythmia or cerebral circulatory insufficiency. In the antitumourfield, these compounds may be useful as anticancer potentiation agents.

There may be mentioned, as particularly representative compounds of thisseries of aminoalkoxyphenylsulphonyl derivatives:

1-methyl-3-isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propoxy}phenylsulphonyl]indoleand its pharmaceutically acceptable salts (Compound A).

1-methyl-3-isopropyl-2-[4-{3-[N-methyl-N-(3,5-dimethoxy-β-phenethyl)amino]propoxy}phenylsulphonyl]indoleand its pharmaceutically acceptable salts (Compound B).

2-[4-{3-[N-Methyl-N-(3,4-dimethoxy-β-phenethyl)amino]-propoxy}phenylsulphonyl]-5-chloro-3-isopropyl-1-methyl-indoleand its pharmaceutically acceptable salts (Compound C).

There has been reported, in the abovementioned patents, a process forthe preparation of heterocyclic aminoalkoxyphenylsulphonyl derivativesstarting from heterocyclic 4-hydroxyphenylsulphonyl derivatives,especially 4-hydroxyphenylsulphonyl derivatives of benzofuran,benzothiophene or indole. Additionally, there has been mentioned thereina method for the synthesis of these 4-hydroxyphenylsulphonylderivatives. This especially includes an oxidation reaction of aheterocyclic 4-methoxyphenylthio derivative by means of3-chloroperbenzoic acid.

Patent Application EP-A-0,302,793 describes, for example, the 4-stagesynthesis of 3-isopropyl-1-methyl-2-(4-hydroxyphenylsulphonyl)indolestarting from 3-isopropylindole according to a process involving anoxidation reaction of this type.

This process consists in:

a) coupling 3-isopropylindole with 4-methoxybenzenethiol to give3-isopropyl-2-(4-methoxyphenylthio)indole (yield: 72% of pure product);

b) oxidising this compound with 3-chloroperbenzoic acid to give3-isopropyl-2-(4-methoxyphenylsulphonyl)indole (yield: 90%);

c) methylating the compound obtained by means of methyl iodide in thepresence of sodium hydride, which provides1-methyl-3-isopropyl-2-(4-methoxyphenylsulphonyl)indole (yield: 85%);

d) O-deprotecting this compound by means of 2-mercaptoethanol/sodiumhydride to finally produce the desired compound (yield: 45.9%).

Consequently, 3-isopropyl-1-methyl-2-(4-hydroxyphenylsulphonyl)indolecan be synthesised according to this process with but a low overallyield of approximately 28% from 3-isopropylindole.

Additionally, the use of 2-mercaptoethanol leaves a nauseating smell inthe 4-hydroxyphenylsulphonyl derivative of formula II, a smell which isfound in the final aminoalkoxyphenylsulphonyl derivative of formula III.

The method thus described is especially characterised by the use of anoxidation stage of a phenylthio derivative containing a protectedhydroxyl radical, in this case a methoxy radical, a protected hydroxylradical which it is necessary to deprotect subsequently in the processso as to regenerate the free hydroxyl.

This use according to an oxidation/deprotection pair can be explained bythe fact that the free hydroxyl functional group is well known to besensitive to oxidising agents since it is capable of being oxidisedfairly easily [Methoden der Organischen Chemie (Houben-Weyl), BandV1/1c--Phenole Teil 2, page 1121].

The search for an industrial process for the preparation of heterocyclic4-hydroxyphenylsulphonyl derivatives of formula II using readilyavailable and inexpensive synthetic intermediates with a satisfactoryyield of final product remains of undeniable interest.

Now, it has been surprisingly discovered, according to the invention,that it is possible to produce heterocyclic 4-hydroxyphenylsulphonylindole derivatives, especially 2- or 3-(4-hydroxyphenylsulphonyl)derivatives, with excellent yields by oxidation of heterocyclicphenylthio derivatives containing not a protected hydroxyl radical but afree hydroxyl radical.

According to the invention, the compounds of formula II are prepared byoxidising a phenylthio derivative of formula I by means of a suitableoxidising agent such as, for example, 3-chloroperbenzoic acid ormagnesium monoperphthalate, and in an a suitable solvent, which providesthe desired compounds.

Generally, the oxidation takes place at a temperature between -5° C. androom temperature, preferably at a temperature between 0° C. and roomtemperature.

As for the solvent, it can be a polar solvent containing an amido group,for example N,N-dimethylformamide, N,N-dimethylacetamide,2-methylpyrrolidone or hexamethylphosphoric triamide, a lower alcohol,for example methanol or ethanol, or also a nitrile, such asacetonitrile.

N,N-Dimethylformamide constitutes a particularly preferred solvent.

Generally, 2 to 2.5 equivalents of oxidising agent, preferably3-chloroperbenzoic acid or magnesium monoperphthalate, are used perequivalent of compound of formula I.

Additionally, it is possible to envisage buffering the reaction mixtureby introducing a weak base such as an alkali metal or alkaline-earthmetal carbonate or bicarbonate.

The compounds of formula I can very advantageously give access to thecompounds of formula II while avoiding the disadvantages of the priorprocesses.

In effect, the formation of a 4-hydroxyphenylsulphonyl chain from4-hydroxyphenylthio derivatives of formula I can be carried out by meansof a single reaction, in contrast to the prior processes which requirethe use of a two-fold reaction, that is to say first an oxidation andthen a deprotection of the hydroxyl radical.

Additionally, the compounds of formula I make possible the synthesis ofcompounds of formula II with particularly advantageous yieldsconsiderably greater than those obtained according to the priortechnique.

For example, 1-methyl-3-isopropyl-2-(4-hydroxyphenylsulphonyl)indole canbe prepared from 3-isopropylindole via2-(4-hydroxyphenylthio)-1-methyl-3-isopropylindole by using threestages, in contrast to the prior technique which requires four stages inall. Moreover, the overall yields obtained according to the inventionprove to be greater than those provided by the known processes sincethey are of the order of 65 % to 70 % from 3-isopropylindole.

Consequently, 4-hydroxyphenylthio derivatives of formula I are alsowithin the invention, as novel industrial products, useful especially assynthetic intermediates, for example for the preparation of4-hydroxyphenylsulphonyl derivatives of formula II.

The compounds of formula I can be obtained by reacting a compound ofgeneral formula: ##STR7## in which R, R₃ and X have the same meaning asabove, with a thiophenol of general formula: ##STR8## in which R₁ and R₂have the same meaning as above, in a suitable solvent such as an aqueoussolvent containing a (C₁ -C₄) alcohol, for example ethanol, or an amidesuch as N,N-dimethylformamide or hexamethylphosphoric triamide, in thepresence of iodine and preferably at the reflux temperature of thereaction mixture, to produce the desired compounds.

The compounds of formula IV and V are known compounds which can beobtained according to known methods.

For example, the compounds of formula IV in which X represents a radical--NR₄ --, in which R₄ is other than hydrogen, can be obtained bytreating a compound of formula IV in which X represents --NH--,optionally in the form of a metal derivative, with a halide of generalformula:

    Hal-R.sub.4                                                VI

in which Hal represents a halogen atom, for example iodine, and R₄ hasthe same meaning as above except for hydrogen.

Preferentially, a metal derivative of the compound of formula IV inwhich X represents --NH-- is used, which metal derivative is obtained bytreating the compound of formula IV in question in which X represents--NH-- with an alkali metal hydride or alkoxide, such as sodium hydrideor potassium tert-butoxide.

As shown above, the 4-hydroxyphenylthio derivatives of formula I can beused for the preparation of aminoalkoxyphenylsulphonyl derivatives offormula III.

Consequently, 4-hydroxyphenylthio derivatives of formula I are alsowithin the invention as intermediates for the final synthesis ofaminoalkoxyphenylsulphonyl derivatives of formula III, in particular forthe synthesis of Compounds A, B or C.

For example, it is possible to prepare the compounds of formula IIIstarting from a 4-hydroxyphenylsulphonyl derivative of formula II itselfobtained according to the invention from the 4-hydroxyphenylthioderivative of formula I, by use of a process containing the followingsequence of stages:

a) coupling the compound of formula II, in the presence of a basicagent, with a dihaloalkane of general formula:

    Hal-A-Hal                                                  VII

in which A has the same meaning as above and Hal represents a halogenatom, preferably bromine, at reflux in a suitable solvent, generally apolar or nonpolar solvent such as methyl ethyl ketone,N,N-dimethylformamide, benzene, toluene or a xylene, or else

b₁) coupling a halogenated alcohol of general formula:

    Hal-A-OH                                                   VIII

in which A and Hal have the same meaning as above, in a solvent such asN,N-dimethylformamide and in the presence of a basic agent, and thencoupling the substituted alcohol obtained with a halide of generalformula:

    Hal-W                                                      IX

in which Hal has the same meaning as above and W represents a (C₁ -C₄)alkylsulphonyl, for example methanesulphonyl, or (C₆ -C₁₀)arylsulphonyl, for example phenylsulphonyl or p-toluenesulphonyl,radical, in an acid-accepting solvent, for example pyridine, or else

b₂) heating at reflux with an epihalohydrin, such as epichlorohydrin, inthe presence of a basic agent and in a polar solvent such as methylethyl ketone, to produce the heterocyclic sulphonyl derivatives ofgeneral formula: ##STR9## in which R, R₁, R₂, R₃ and X have the samemeaning as above and Z represents a radical of general formula:

    --A--Z.sub.1

in which A has the same meaning as above and Z₁ represents a halogenatom or a (C₁ -C4) alkylsulphonyloxy or (C₆ -C₁₀) arylsulphonyloxyradical.

The basic agent used during the treatment of the compound of formula IIis generally an alkali metal carbonate, for example potassium carbonate,an alkali metal hydroxide such as sodium hydroxide or potassiumhydroxide, an alkali metal hydride such as sodium hydride, or an alkalimetal alkoxide, for example sodium methoxide or sodium ethoxide.

The derivative of formula X is then reacted with an amine of generalformula:

    H-Am                                                       XI

in which Am has the same meaning as above, the reaction taking place inthe presence of an acid acceptor and in a suitable solvent, generally apolar solvent such as an alcohol, for example butanol, a ketone such asmethyl ethyl ketone, an aromatic hydrocarbon, for example benzene,toluene or a xylene, or even an excess of amine of formula XI, toproduce the compounds of formula III in the form of a free base, whichcan be reacted, if desired, with a suitable acid to form apharmaceutically acceptable salt of this compound.

According to an alternative method, it is possible to use the compoundsof formula II obtained according to the invention by directly treatingsuch a compound with a halide of general formula:

    Hal-A-Am                                                   XII

in which Hal and Am have the same meaning as above and A represents a(C₂ -C₅) alkylene radical, the reaction being carried out in thepresence of a basic agent such as an alkali metal carbonate, for examplepotassium carbonate, an alkali metal hydroxide such as sodium hydroxideor potassium hydroxide, an alkali metal hydride such as sodium hydride,or an alkali metal alkoxide, for example sodium methoxide or sodiumethoxide, to produce the compounds of formula III in which A representsa (C₂ -C₅) alkylene radical, which compound can be reacted, if desired,with a suitable acid to form a pharmaceutically acceptable salt of thiscompound.

The following, non-limiting examples illustrate the preparation of thecompounds of the invention:

EXAMPLE 1 Preparation of2-(4-hydroxyphenylthio)-3-isopropyl1-methylindole

a) 3-Isopropyl-1-methylindole

A solution of 25 g (0.157 mol) of 3-isopropylindole in 200 ml of benzeneis added to a suspension of 21.1 g (0.172 mol) of potassiumtert-butoxide with good stirring.

24.51 g (0.172 mol) of methyl iodide are then slowly added. Stirring iscontinued at room temperature for 20 h.

A water/crushed ice mixture is added and the benzene fraction isseparated. This fraction is washed twice with water, dried overanhydrous sodium sulphate, filtered and the solvent driven off on arotary evaporator, which provides an oily residue.

In this way, 27 g of 3-isopropyl-1-methylindole are obtained. Yield:100%.

b) 2-(4-Hydroxyphenylthio)-3-isopropyl-1-methylindole

27 g (0.155 mol) of 3-isopropyl-1-methylindole and 21.7 g (0.172 mol) of4-hydroxybenzenethiol are dissolved in 250 ml of ethanol and 125 ml ofwater. The whole is placed under a nitrogen atmosphere and a solution of43.65 g (0.172 mol) of iodine in ethanol is slowly added. The mixture isheated at reflux for 2 hours, cooled and poured into ice-cold water.Extraction is carried out with ethyl acetate and the extract is washedwith water and dried over anhydrous sodium sulphate. Filtration is thencarried out, the solvent is evaporated on a rotary evaporator andpurification is carried out by column chromatography (eluent: 7/3heptane/dichloroethane).

In this way, there is obtained 33.9 g of2-(4-hydroxyphenylthio)-3-isopropyl-1-methylindole.

Yield: 73.5%

M.p.: 89°-90° C.

Purity: 99.3%.

EXAMPLE 2 Preparation of 3-(4-hydroxyphenylthio)-2-isopropylindole

3.2 g (0.02 mol) of 2-isopropylindole and 2.5 g (0.02 mol) of4-hydroxybenzenethiol are dissolved in 80 ml of ethanol.

40 ml of water are added, the mixture is stirred and then a solution of5 g (0.04 mol) of iodine in ethanol is introduced dropwise. The oil thusformed is then poured into 400 ml of water and the mixture is thenstirred while cooling until the oil has solidified. The product isfiltered and washed on a filter. The product is then dried under vacuumat a temperature of 60° C., which provides 5.6 g of the expectedproduct. Recrystallisation is then carried out from 250 ml of a 7/3heptane/toluene mixture.

In this way, there is obtained 4.2 g of3-(4-hydroxyphenylthio)-2-isopropylindole in the form of an insolubleresin.

Yield: 74.2%

M.p.: 116° C.

The following non-limiting examples illustrate the use of the compoundsof the invention:

EXAMPLE I Preparation of2-(4-hydroxyphenylsulphonyl)-3-isopropyl1-methylindole

13.17 g (0.044 mol) of2-(4-hydroxyphenylthio)-3-isopropyl-1-methylindole are dissolved in 70ml of N,N-dimethylformamide. The solution is stirred and cooled to 0° C.and then a solution of 21.7 g (0.088 mol) of 70% 3-chloroperbenzoic acidis slowly (2 h) added. The temperature of the mixture is left to returnto room temperature and stirring of the reaction mixture is continuedfor 20 h while monitoring the development of the reaction (sulphide,sulphoxide, sulphone) by T.L.C. The mixture is run into ice-cooled waterand the precipitate formed is filtered and washed on the filter with asodium bicarbonate solution, ending with water. Purification is thencarried out by chromatography on a silica column (eluent: dichloroethanecontaining 2% of methanol).

In this way, there is obtained 9 g of2-(4-hydroxyphenylsulphonyl)-3-isopropyl-1-methylindole.

Yield: 62.1%.

M.p.: 188° C.

EXAMPLE II Preparation of2-(4-hydroxyphenylsulphonyl)-3-isopropyl-1-methylindole

By using the same process as that described in Example I but by adding,over 2 h at room temperature, 2.1 mol of 3-chloroperbenzoic acid to 1mol of 2-(4-hydroxyphenylthio)-3-isopropyl-1-methylindole inN,N-dimethylformamide and by keeping the reaction mixture stirring for24h at room temperature, there is obtained2-(4-hydroxyphenylsulphonyl)-3-isopropyl-1-methylindole with a yield of62%.

EXAMPLE III Preparation of2-(4-hydroxyphenylsulphonyl)-3-isopropyl1-methylindole

By using the same process as that described in Example I but by adding,over 5 h at 10° C., 2.4 mol of 3-chloroperbenzoic acid to 1 mol of2-(4-hydroxyphenylthio)-3-isopropyl-1-methylindole inN,N-dimethylformamide and by keeping the reaction mixture stirring for48 h at room temperature, there is obtained2-(4-hydroxyphenylsulphonyl)-3-isopropyl-1-methylindole with a yield of80%.

EXAMPLE IV Preparation of2-(4-hydroxyphenylsulphonyl)-3-isopropyl1-methylindole

By using the same process as that described in Example I but by adding2.4 mol of 3-chloroperbenzoic acid to 1 mol of2-(4-hydroxyphenylthio)-3-isopropyl-1-methylindole inN,N-dimethylformamide, at the rate of 1.1 mol over 0.5 h at 10° C. andthen 1.3 mol over 5 h at 10° C. and by keeping the reaction mixturestirring for 48 h at room temperature, there is obtained2-(4-hydroxyphenylsulphonyl)-3-isopropyl-1-methylindole with a yield of88%.

EXAMPLE V Preparation of the acid oxalate of 1-methyl-3-isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propoxy}phenylsulphonyl]indole

29 g (0.21 mol) of anhydrous and finely ground potassium carbonate areadded to a mixture of 9.9 g (0.003 mol) of2-(4-hydroxyphenylsulphonyl)-3-isopropyl-1-methylindole in 165 ml ofN,N-dimethylformamide. The mixture is stirred for 0.5 hour and 13.3 g(0.033 mol) of the acid oxalate of 90% 1-chloro-3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propane are added.

The mixture is heated at 100° C. for 1 hour and is left to return toroom temperature with stirring. It is poured into 450 ml of water andice and the mixture is stirred for 0.25 hour. Extraction is carried outwith 3 times 150 ml of diethyl ether, and the extracts are washed twicewith 150 ml of water and dried over sodium sulphate. 3.5 g of oxalicacid, dissolved in 50 ml of ethyl ether, are added to the ether solutionobtained and the mixture is left to crystallise for 24 hours. Thecrystals are filtered, washed with isopropyl ether and dried undervacuum at 50° C.

In this way, there is obtained the acid oxalate of1-methyl-3-isopropyl-2-[4-{3-[N-methyl-N-(3,4-dimethoxy-β-phenethyl)amino]propoxy}phenylsulphonyl]indole.

Yield: 90%

M.p.: 94° C.

Example VI Preparation of 3-(4-hydroxyphenylsulphonyl)2-isopropylindole

0.36 g (0.00127 mol) of 3-(4-hydroxyphenylthio)2-isopropylindole aredissolved in 5 ml of N,N-dimethylformamide. The solution is cooled to 0°C. (ice bath) and a solution of 0.62 g (0.00254 mol) of 70%3-chloroperhenzoic acid in 2 ml of N,N-dimethylformamide is addeddropwise.

Stirring is continued at room temperature for 24 hours and then themixture is run into ice-cold water.

The sticky precipitate thus formed is extracted with theyl acetate andthe solution is washed with an aqueous sodium bicarbonate solution andthen with water. The solution is dried over sodium sulphate, filteredand the solvent is driven off on a rotary evaporator, which provides a0.5 g residue which is crystallised from an ethanol/water mixture.

In this way, there is obtained 0.38 g of3-(4-hydroxyphenylsulphonyl)-2-isopropylindole

Yield:95%.

M.p.: 152° C.

We claim:
 1. Process for the preparation of a 4-hydroxyphenylsulfonylcompound of the general formula: ##STR10## in which: R₁ and R₂, whichare identical or different, are selected from the group consisting ofhydrogen, methyl, ethyl and halogenR is selected from the groupconsisting of (C₁ -C₆) alkyl, (C₃ -C₆) cycloalkyl and phenyl, R₃ isselected from the group consisting of hydrogen and halogen, X isselected from the group consisting of --O--, --S-- and --NR4-- in whichR₄ is selected from the group consisting of hydrogen and (C₁ -C₄)alkyl,wherein a 4-hydroxyphenylthio compound of general formula:##STR11## in which R, R₁, R₂, R₃ and X have the same meaning as statedabove, is oxidized in a solvent by means of an oxidizing agent toproduce the desired compound.
 2. Process according to claim 1, whereinthe oxidizing agent is 3-chloroperbenzoic acid or magnesiummonoperphthalate.
 3. Process according to claim 1, wherein from 2 to 2.5equivalents of oxidizing agent are used per equivalent of phenylthiocompound of formula I.
 4. Process according to claim 1, wherein theoxidation takes place at a temperature between -5° C. and roomtemperature.
 5. Process according to claim 1, wherein the oxidationtakes place in a polar solvent.
 6. Process according to claim 5, whereinthe solvent is selected from N, N-dimethylformamide,hexamethylphosphoric triamide, acetonitrile and (C₁ -C₄) alcohol.
 7. Theprocess according to claim 1, wherein the compound of general formula Iis made by a process comprising the step of reacting a compound ofgeneral formula: ##STR12## in which R, R₃ and X have the same meaning asin claim 1, with a thiophenol of general formula: ##STR13## in which R₁and R₂ have the same meaning as in claim 1, in a solvent in the presenceof iodine and at the reflux temperature of the reaction mixture, toproduce the desired compound.
 8. Process according to claim 7, whereinthe solvent is an aqueous solution of a (C₁ -C₄) alcohol or of an amide.